Systems, devices, and associated methods for neuromodulation with enhanced nerve targeting

ABSTRACT

Systems and methods for neuromodulation therapy are disclosed herein. A method in accordance with embodiments of the present technology can include, for example, positioning a plurality of reference electrodes at the skin of a human patient and intravascularly positioning a plurality of ablation electrodes within a blood vessel lumen at a treatment site. The method can include obtaining impedance measurements between different combinations of the reference electrodes and the ablation electrodes and, based on the impedance measurements, identifying two or more electrode groups for treatment, where at least two of the electrode groups include a different one of the reference electrodes and a different one of the ablation electrodes.

CROSS-REFERENCE

The present application claims the benefit of U.S. Provisional PatentApplication No. 62/588,215, filed Nov. 17, 2017, the disclosure of whichis incorporated herein by reference in its entirety.

TECHNICAL FIELD

The present technology is related to neuromodulation. In particular,various embodiments of the present technology are related to systems andmethods for neuromodulation with enhanced nerve targeting.

BACKGROUND

The sympathetic nervous system (SNS) is a primarily involuntary bodilycontrol system typically associated with stress responses. Fibers of theSNS extend through tissue in almost every organ system of the human bodyand can affect characteristics such as pupil diameter, gut motility, andurinary output. Such regulation can have adaptive utility in maintaininghomeostasis or in preparing the body for rapid response to environmentalfactors. Chronic over-activation of the SNS, however, is a commonmaladaptive response that can drive the progression of many diseasestates. Excessive activation of the renal SNS in particular has beenidentified experimentally and in humans as a likely contributor to thecomplex pathophysiology of arrhythmias, hypertension, states of volumeoverload (e.g., heart failure), and progressive renal disease.

Sympathetic nerves of the kidneys terminate in the renal blood vessels,the juxtaglomerular apparatus, and the renal tubules, among otherstructures. Stimulation of the renal sympathetic nerves can cause, forexample, increased renin release, increased sodium reabsorption, andreduced renal blood flow. These and other neural-regulated components ofrenal function are considerably stimulated in disease statescharacterized by heightened sympathetic tone. For example, reduced renalblood flow and glomerular filtration rate as a result of renalsympathetic efferent stimulation is likely a cornerstone of the loss ofrenal function in cardio-renal syndrome, (i.e., renal dysfunction as aprogressive complication of chronic heart failure). Pharmacologicstrategies to thwart the consequences of renal sympathetic stimulationinclude centrally-acting sympatholytic drugs, beta blockers (e.g., toreduce renin release), angiotensin-converting enzyme inhibitors andreceptor blockers (e.g., to block the action of angiotensin II andaldosterone activation consequent to renin release), and diuretics(e.g., to counter the renal sympathetic mediated sodium and waterretention). These pharmacologic strategies, however, have significantlimitations including limited efficacy, compliance issues, side effects,and others.

BRIEF DESCRIPTION OF THE DRAWINGS

Many aspects of the present disclosure can be better understood withreference to the following drawings. The components in the drawings arenot necessarily to scale. Instead, emphasis is placed on illustratingclearly the principles of the present disclosure.

FIG. 1 is a table showing the electrical conduction properties ofdifferent types of tissue.

FIG. 2 is a schematic illustration showing the different electricalfields generated by ablation electrodes positioned at differentlocations within the lumen of a renal artery.

FIG. 3 is a partially schematic illustration of a neuromodulation systemconfigured in accordance with some embodiments of the presenttechnology.

FIGS. 4 and 5 illustrate modulating renal nerves with the system of FIG.3 in accordance with some embodiments of the present technology.

FIG. 6 is a block diagram illustrating a method of using ablationelectrodes and reference electrodes to create an impedance map inaccordance with some embodiments of the present technology.

FIG. 7 is a block diagram illustrating a method of modulating renalnerves in accordance with some embodiments of the present technology.

FIGS. 8A and 8B are schematic representations showing the effects ofdifferent electrode groupings on lesion size, shape, and position.

FIG. 9 is a conceptual illustration of the sympathetic nervous system(SNS) and how the brain communicates with the body via the SNS.

FIG. 10 is an enlarged anatomic view of nerves innervating a left kidneyto form the renal plexus surrounding the left renal artery.

FIGS. 11 and 12 are anatomic and conceptual views, respectively, of ahuman body depicting neural efferent and afferent communication betweenthe brain and kidneys.

FIGS. 13 and 14 are anatomic views of the arterial vasculature andvenous vasculature, respectively, of a human.

DETAILED DESCRIPTION

The present technology is directed to devices, systems, and methods forneuromodulation, such as renal neuromodulation. In some embodiments, thepresent technology includes methods for selecting combinations ofablation electrodes and surface electrodes (e.g., reference electrodes)for the purpose of influencing the size, shape, and directionality ofthe electrical fields emanating from the ablation electrodes duringtreatment. The spatial and directional properties of the ablative energydirectly affect the three-dimensional shape of the lesion(s) (i.e.,damaged tissue) created by the ablative energy, as well as the positionof the lesion(s) relative to the artery or other blood vessel in whichthe ablation electrodes are positioned during treatment. Accordingly,the present technology leverages the spatial relationships betweenablation electrodes and reference electrodes to better concentrate theablative energy on the targeted nerves, for a given local anatomy, andis thus expected to improve efficacy of neuromodulation treatment whileminimizing/inhibiting the delivery of ablative energy to non-targettissue. As discussed in greater detail below, therapeutically-effectiverenal neuromodulation can include rendering neural fibers inert,inactive, or otherwise completely or partially reduced in function.

Specific details of several embodiments of the technology are describedbelow with reference to FIGS. 1-14. The embodiments can include, forexample, modulating nerves proximate (e.g., at or near) a renal artery,a renal vein, and/or other suitable structures. Although many of theembodiments are described herein with respect to electrically-inducedapproaches, other treatment modalities in addition to those describedherein are within the scope of the present technology. Additionally,other embodiments of the present technology can have differentconfigurations, components, or procedures than those described herein. Aperson of ordinary skill in the art, therefore, will accordinglyunderstand that the technology can have other embodiments withadditional elements and that the technology can have other embodimentswithout several of the features shown and described below with referenceto FIGS. 1-14.

As used herein, the terms “distal” and “proximal” define a position ordirection with respect to the treating clinician or clinician's controldevice (e.g., a handle assembly). “Distal” or “distally” can refer to aposition distant from or in a direction away from the clinician orclinician's control device. “Proximal” and “proximally” can refer to aposition near or in a direction toward the clinician or clinician'scontrol device.

I. Overview

Some conventional renal denervation devices employ a multi-electrode,unipolar electrode system that delivers radio frequency (RF) energy tothe endovascular surface of the renal artery (or other blood vessels)for the purpose of ablating nerves at the extravascular surface of theartery (or other blood vessels). An example of one such system is themulti-electrode Symplicity Spyral™ catheter along with a Symplicity G3™generator. The catheter and generator are commercially available fromMedtronic, Inc. The shape of the electric field and relative penetrationdepth of current densities strong enough to damage nerve tissue dependon several factors including, among others, the power and duration ofenergy delivery, the geometric shape of the electrodes, the electrodematerial, and the apposition of the electrodes against the vessel wall.The shape and current density of the electric field within the tissuealso depends on the relative conductive properties of the tissue throughwhich the current travels based on the relative three-dimensionalconductivity of each individual tissue. FIG. 1, for example, is a tableshowing the electrical conduction properties of different types oftissue. In general, tissues that contain relatively more fluid, such asinterstitial space, blood vessels, and lymph vessels, tend to conductbetter than tissues with relatively less fluid, such as fat, tendon, andbone. FIG. 2 is a schematic illustration showing the differentelectrical fields generated by ablation electrodes positioned atdifferent locations within the lumen of a renal artery. (Source: Esler;Science Translational Medicine, 29 Apr. 2015, Vol. 7, Issue 285.) Asshown, the veins act as energy sinks and prevent RF energy from reachingthe nerve target, while the lymph nodes and tendons draw the energy butredirect it. Accordingly, each unique electrode placement in a uniquelocation within the artery of a unique individual is expected to createa unique electric field.

II. Neuromodulation Devices, Systems, and Methods of Use

FIG. 3 is a partially schematic illustration of a neuromodulation system100 (“system 100”) configured in accordance with some embodiments of thepresent technology. As shown in FIG. 3, the system 100 includes aneuromodulation catheter 102, a console 104, and a cable 106 extendingtherebetween. The system 100 further includes a plurality of patch orreference electrodes 200 (e.g., return or neutral electrodes) configuredto be positioned on the patient's skin and electrically coupled to theconsole 104.

The neuromodulation catheter 102 can include an elongated shaft 108having a proximal portion 108 b, a distal portion 108 a, a handle 110operably connected to the shaft 108 at the proximal portion 108 b, and aneuromodulation assembly 120 operably connected to the shaft 108 at thedistal portion 108 a. The shaft 108 and the neuromodulation assembly 120can be 2, 3, 4, 5, 6, or 7 French or another suitable size. As shownschematically in FIG. 3, the neuromodulation assembly 120 can include asupport structure 122 carrying an array of two or more ablationelectrodes 124 spaced apart along the shaft 108. The ablation electrodes124 can be configured to apply electrical stimuli (e.g., RF energy) totarget sites at or proximate to vessels within a patient, temporarilystun nerves, deliver neuromodulation energy to target sites, and/ordetect local tissue impedance. In some embodiments, the ablationelectrodes 124 may be shaped to improve/enhance contact with the vesselwall. For example, the ablation electrodes 124 may be shaped such thatan outer or engagement surface of the individual electrodes more closelymatches the shape of the vessel wall to ensure maximum wall contact (andthereby enhance reliable energy delivery).

The distal portion 108 a of the shaft 108 is configured to be movedwithin a lumen of a human patient and locate the neuromodulationassembly 120 at a target site within or otherwise proximate to thelumen. For example, the shaft 108 can be configured to position theneuromodulation assembly 120 within a blood vessel, a duct, an airway,or another naturally occurring lumen within the human body. In certainembodiments, intravascular delivery of the neuromodulation assembly 120includes percutaneously inserting a guide wire (not shown) into a bodylumen of a patient and moving the shaft 108 and/or the neuromodulationassembly 120 along the guide wire until the neuromodulation assembly 120reaches a target site (e.g., a renal artery). For example, the distalend of the neuromodulation assembly 120 may define a passageway forengaging the guide wire for delivery of the neuromodulation assembly 120using over-the-wire (OTW) or rapid exchange (RX) techniques. In otherembodiments, the neuromodulation catheter 102 can be a steerable ornon-steerable device configured for use without a guide wire. In stillother embodiments, the neuromodulation catheter 102 can be configuredfor delivery via a guide catheter or sheath (not shown).

Once positioned at the target site, the neuromodulation assembly 120 canbe configured to apply stimuli, detect resultant hemodynamic responses,and provide or facilitate neuromodulation therapy at the target site(e.g., using the ablation electrodes 124 and/or other energy deliveryelements). For example, the neuromodulation assembly 120 can detectvessel impedance via the ablation electrodes 124, blood flow via a flowsensing element (e.g., a Doppler velocity sensing element), local bloodpressure within the vessel via a pressure transducer or other pressuresensing element, and/or other hemodynamic parameters. In someembodiments, the neuromodulation assembly 120 can detect vesselimpedance via sensing elements separate from the ablation electrodes124. In such embodiments, the neuromodulation assembly 102 may detectimpedance with one or both of the sensing elements and the ablationelectrodes 124. The detected responses can be transmitted to the console104 and/or another device external to the patient. The console 104 canbe configured to receive and store the recorded impedance measurementsfor further use by a clinician or operator. For example, a clinician canuse the impedance measurements received by the console 104 to selectcombinations of ablation electrodes and reference electrodes, asdescribed in greater detail below.

The console 104 can be configured to control, monitor, supply, and/orotherwise support operation of the neuromodulation catheter 102. Theconsole 104 can further be configured to generate a selected form and/ormagnitude of energy for delivery to tissue at the target site via theneuromodulation assembly 120, and therefore the console 104 may havedifferent configurations depending on the treatment modality of theneuromodulation catheter 102. For example, the console 104 can includean energy generator (not shown) configured to generate RF energy. Insome embodiments, the system 100 may be configured to deliver amonopolar electric field via one or more of the ablation electrodes 124and/or bipolar energy between selected combination(s) of ablationelectrodes 124. The reference electrodes 200 may be electricallyconnected to the console 104 and positioned at the skin of the patientat multiple locations to help direct and shape the electric fieldgenerated by the ablation electrodes 124 (as discussed in greater detailbelow with reference to FIG. 5). In embodiments including multipleablation electrodes 124, the ablation electrodes 124 may deliver powerindependently (i.e., may be used in a monopolar fashion), eithersimultaneously, selectively, or sequentially, and/or may deliver powerbetween any desired combination of the ablation electrodes 124 (i.e.,may be used in a bipolar fashion). In addition, an operator optionallymay be permitted to choose which ablation electrodes 124 are used forpower delivery based, at least in part, on local anatomic features orother specific feedback, in order to form highly customized lesion(s)within the renal artery, as desired. One or more sensing elements (notshown), such as one or more temperature (e.g., thermocouple, thermistor,etc.), pressure, optical, flow, chemical, and/or other sensing elements,may be located proximate to, within, or integral with the ablationelectrodes 124. The sensing element(s) and the ablation electrodes 124can be connected to one or more supply wires (not shown) that transmitsignals from the sensing element(s) and/or convey energy to the ablationelectrodes 124. Feedback from such signals may processed by the module,presented to the operator, and used by the operator to inform on whichavailable electrode-reference combination(s) to choose.

In various embodiments, the system 100 can further include a controller114 communicatively coupled to the neuromodulation catheter 102. Thecontroller 114 can be configured to initiate, terminate, and/or adjustoperation of one or more components (e.g., the ablation electrodes 124)of the neuromodulation catheter 102 directly and/or via the console 104.For example, as described in greater detail below, the controller 114may be configured to continuously or intermittently monitor theimpedance between each of the ablation electrodes 124 and each of thereference electrodes 200 and, based on those measurements, selectparticular ablation electrode 124/reference electrode 200 groupings thatprovide optimal electric fields for efficacious neuromodulation therapy.The controller 114 may also be configured to further adjust deliveredpower based on anatomical and/or sensor feedback.

In some embodiments, the controller 114 can be a component separatedfrom the console 104, such as within the handle 110, along the cable106, etc. The controller 114 can be configured to execute one or moreautomated control algorithms and/or to receive control instructions froman operator. Further, the console 104 can be configured to providefeedback to an operator before, during, and/or after a treatmentprocedure via an evaluation/feedback algorithm 116 (e.g., such aschanging ablation electrode 124/reference electrode 200 groupings inresponse to impedance measurements).

FIG. 4 (with additional reference to FIG. 3) illustrates gaining accessto renal nerves in accordance with some embodiments of the presenttechnology. The neuromodulation catheter 102 provides access to therenal plexus RP through an intravascular path P, such as a percutaneousaccess site in the femoral (illustrated), brachial, radial, or axillaryartery to a targeted treatment site within a respective renal artery RA.By manipulating the proximal portion 108 b of the shaft 108 from outsidethe intravascular path P, a clinician may advance the shaft 108 throughthe sometimes tortuous intravascular path P and remotely manipulate thedistal portion 108 a (FIG. 3) of the shaft 108. In the embodimentillustrated in FIG. 4, the neuromodulation assembly 120 is deliveredintravascularly to the treatment site using a guide wire 136 in an OTWtechnique. As noted previously, the distal end of the neuromodulationassembly 120 may define a passageway for receiving the guide wire 136for delivery of the neuromodulation catheter 102 using either OTW or RXtechniques. At the treatment site, the guide wire 136 can be at leastpartially withdrawn or removed, and the neuromodulation assembly 120 cantransform or otherwise be moved to a deployed arrangement for recordingneural activity and/or delivering energy at the treatment site. In otherembodiments, the neuromodulation assembly 120 may be delivered to thetreatment site within a guide sheath (not shown) with or without usingthe guide wire 136. When the neuromodulation assembly 120 is at thetarget site, the guide sheath may be at least partially withdrawn orretracted and the neuromodulation assembly 120 can be transformed intothe deployed arrangement. In still other embodiments, the shaft 108 maybe steerable itself such that the neuromodulation assembly 120 may bedelivered to the treatment site without the aid of the guide wire 136and/or guide sheath.

Image guidance, e.g., computed tomography (CT), fluoroscopy,intravascular ultrasound (IVUS), optical coherence tomography (OCT),intracardiac echocardiography (ICE), or another suitable guidancemodality, or combinations thereof, may be used to aid the clinician'spositioning and manipulation of the neuromodulation assembly 120. Forexample, a fluoroscopy system (e.g., including a flat-panel detector,x-ray, or c-arm) can be rotated to accurately visualize and identify thetarget treatment site. In other embodiments, the treatment site can bedetermined using IVUS, OCT, and/or other suitable image mappingmodalities that can correlate the target treatment site with anidentifiable anatomical structure (e.g., a spinal feature) and/or aradiopaque ruler (e.g., positioned under or on the patient) beforedelivering the neuromodulation assembly 120. Further, in someembodiments, image guidance components (e.g., IVUS, OCT) may beintegrated with the neuromodulation catheter 102 and/or run in parallelwith the neuromodulation catheter 102 to provide image guidance duringpositioning of the neuromodulation assembly 120. For example, imageguidance components (e.g., IVUS or OCT) can be coupled to theneuromodulation assembly 120 to provide three-dimensional images of thevasculature proximate the target site to facilitate positioning ordeploying the multi-electrode assembly within the target renal bloodvessel.

As shown schematically in FIG. 5, a plurality of reference electrodes200 (individually labeled A-Z) may be positioned about the patient'sabdominal area while the neuromodulation assembly 120 is positionedwithin the patient's blood vessel V (e.g., renal artery). The referenceelectrodes 200 may be positioned on the patient before, during, and/orafter placement of the neuromodulation assembly 120 in the blood vesselV. In some embodiments, the neuromodulation assembly 120 may includefirst, second, third, and fourth ablation electrodes 124 a-124 d(referred to collectively as “ablation electrodes 124”), for example asshown in FIG. 5. In other embodiments, however, the neuromodulationassembly 120 may include more or fewer ablation electrodes 124 (e.g.,two ablation electrodes, three ablation electrodes, five ablationelectrodes, six ablation electrodes, etc.).

Although the reference electrodes 200 are shown positioned at theabdomen and upper leg region of the patient, in some embodiments one ormore of the reference electrodes 200 may be positioned elsewhere on thepatient's body, such as the patient's arms, lower legs, and upper torso,as well as at the backside of the patient. In additional embodiments,one or more reference electrodes 200 may also be carried on the catheter102, guide catheter, guide wire, introducer, and/or a separate referenceelectrode catheter configured to be positioned at a desired locationwithin the patient's vasculature (e.g., renal vein, renal artery, etc.)or a suitable body lumen (e.g., ureter). Moreover, any number ofreference electrodes 200 may be used to achieve a desired specific oralternate energy delivery profile, such as one reference electrode, tworeference electrodes, five reference electrodes, 15 referenceelectrodes, 30 reference electrodes, 100 reference electrodes, etc.

FIG. 6 is a block diagram illustrating a method 600 of mapping theelectrical environment surrounding the neuromodulation assembly 120prior to neuromodulation therapy, in accordance with some embodiments ofthe present technology. Referring to FIGS. 5 and 6 together, accordingto some methods of the present technology, a low power signal may besent between one or more of the ablation electrodes 124 and one or moreof the reference electrodes 200 before energy delivery (block 602), andthe resulting impedance of each combination may be measured (e.g., viathe ablation electrodes 124) (block 604) to create a rough impedance mapof the anatomical environment (and its conductivity profile) at or nearthe treatment site (block 606). For example, a low power signal may besent between the first ablation electrode 124 a and each of thereference electrodes (A-Z), and all 26 of those measurements may bestored at the controller 114 (FIG. 3). The same process may be repeatedfor any of the second-fourth ablation electrodes 124 b-d. In someembodiments, impedance measurements may be obtained for less than everycombination of ablation electrode 124 and reference electrode 200. Theobtained impedance measurements can be organized to form an impedancemap that informs the clinician of the effects of the local anatomy onthe shape of the electric field induced between the ablation electrodes124 and reference electrodes 200. Based on the impedance map, as well asimages already obtained of the local anatomy and/or known tissueelectrical conduction properties (see FIG. 1), the clinician may selectparticular reference electrode/ablation electrode combinations tooptimize the direction and/or three-dimensional shape of the electricfield during subsequent energy delivery (block 608). In someembodiments, the controller 114 (FIG. 3) automatically identifiescertain ablation electrode/reference electrode groups based on themapping and/or automatically begins treatment using the identifiedablation electrode/reference electrode groupings. In some embodiments,identification of the optimal ablation electrode 124/reference electrode200 combinations includes comparing (manually and/or automatically bythe controller 114) the impedance measurements to one another and/or toa predetermined threshold. As used herein, a “threshold” refers to asingle value or a range of values. Relatively lower impedance pathways,for example, may indicate a more direct route for RF current from theelectrode to the respective ground electrode, since blood is moreconductive than muscle. Hence, low impedance pathways may be the resultof more current being shunted away via the blood vessel, rather thanbeing forced through the adventitia where the nerves reside.

FIG. 7 is a block diagram illustrating a method 700 of evaluating theefficacy of different electrode groupings via impedance measurementsobtained in real-time during neuromodulation therapy. For example, insome embodiments, with or without generating an impedance map prior toenergy delivery, the clinician may begin neuromodulation therapy (block702) by delivering energy from the ablation electrodes 124 and/or otherenergy delivery elements to target tissue to induce one or more desiredneuromodulating effects on localized regions of the renal artery RA andadjacent regions of the renal plexus RP, which lay intimately within,adjacent to, or in close proximity to the adventitia of the renal arteryRA. The purposeful application of the energy may achieve neuromodulationalong all or at least a portion of the renal plexus RP.

During energy delivery, the controller 114 may continuously orintermittently obtain impedance measurements for a given ablationelectrode 124 relative to each of the reference electrodes 200, andautomatically compare these impedance measurements to one another and/orto a predetermined threshold to determine which reference electrode 200provides the optimal electrical field profile for the ablation electrode124. For example, as shown in FIG. 7, energy delivery may begin witheach ablation electrode 124 grouped with a particular referenceelectrode 200 (block 702). In some embodiments, each ablation electrode124 may be initially grouped with a different reference electrode(s)200, and in some embodiments some or all of the ablation electrodes 124may be initially grouped with the same reference electrode 200. Duringenergy delivery, the controller 114 (FIG. 3) may continuously orintermittently obtain impedance measurements between each ablationelectrode 124 and each of the reference electrodes (A-Z) (block 704) andcompare the impedance measurements obtained for a given ablationelectrode to one another and/or to a predetermined threshold (block706). Based on this comparison, the controller 114 may automaticallyselect the ablation electrode 124/reference electrode 200 grouping thatprovides the optimal electrical field to achieve a desired treatmentprofile. For instance, if the comparison determines that the ablationelectrode 124 is not currently grouped with the reference electrode 200that would provide the optimal current path, the controller 114 mayautomatically stop sending current between the ablation electrode 124and the currently-paired reference electrode 200 and start sendingcurrent between the ablation electrode 124 and the different referenceelectrode 200 (block 708). Likewise, if the comparison determines thatthe ablation electrode 124 is already grouped with the referenceelectrode 200 that provides the optimal current path (based on impedancemeasurements or some other parameter that reflect current usage to infersuccessful energy delivery to the target nerves), the controller 114 maycontinue sending current between the ablation electrode 124 and thepresent reference electrode 200 (block 710). The foregoing process maybe executed (simultaneously or sequentially) for any of the ablationelectrodes 124 a-d.

In other embodiments, the controller 114 may be configured toautomatically toggle the reference electrode(s) between two or moreground patches, regardless of impedance, during treatment. For example,the controller 114 may toggle between various ablationelectrode/reference electrode groups based on predetermined time limits(e.g., 10 second cycles for each combination). In still otherembodiments, the controller 114 may be configured to automaticallyand/or manually toggle between different electrode groupings based onstill other parameters (in addition to, or in lieu of, impedance ortime).

In addition to reference electrode/ablation electrode placement, theneuromodulating effects are generally a function of, at least in part,power, time, contact between the energy delivery elements and the vesselwall, and blood flow through the vessel. The neuromodulating effects mayinclude denervation, thermal ablation, and/or non-ablative thermalalteration or damage (e.g., via sustained heating and/or resistiveheating). Desired thermal heating effects may include raising thetemperature of target neural fibers above a desired threshold to achievenon-ablative thermal alteration, or above a higher temperature toachieve ablative thermal alteration. For example, the target temperaturemay be above body temperature (e.g., approximately 37° C.) but less thanabout 45° C. for non-ablative thermal alteration, or the targettemperature may be about 45° C. or higher for the ablative thermalalteration. Desired non-thermal neuromodulation effects may includealtering the electrical signals transmitted in a nerve.

By way of example, FIGS. 8A and 8B are schematic representations showingthe effects of different ablation electrode 124/reference electrode 200groupings on lesion size, shape, and position. FIG. 8A, for example,shows a lesion L caused by sending neuromodulation current between thefirst ablation electrode 124 a and reference electrode A (positioned ata first location on the patient's body). As shown in FIG. 8A, the lesionL is positioned generally along the right half circumference of theblood vessel V and thus captures a first set of nerves N at that side ofthe vessel V. In comparison, FIG. 8B shows the lesion L caused bysending neuromodulation current between the first ablation electrode 124a and reference electrode M (positioned at a second location on thepatient's body spaced apart from the first location). As shown in FIG.8B, the lesion L is positioned generally along the top halfcircumference of the blood vessel V and thus captures a second set ofnerves N at that side of the vessel V. Also, as shown in FIGS. 8A and8B, in addition to the first and second lesions being located atdifferent positions relative to the blood vessel V, the first and secondlesions are also different shapes and enclose different volumes.

In some embodiments, a temperature at one or more of the ablationelectrodes 124 may be measured (instead of or in addition to measuringimpedance) in addition to or in substitution of impedance. In additionalembodiments, electroencephalogram (EEG) monitoring and/or bloodchemistry may also be utilized to provide real time patient feedbackduring therapy.

III. Renal Neuromodulation

Renal neuromodulation is the partial or complete incapacitation or othereffective disruption of nerves of the kidneys (e.g., nerves terminatingin the kidneys or in structures closely associated with the kidneys). Inparticular, renal neuromodulation can include inhibiting, reducing,and/or blocking neural communication along neural fibers (e.g., efferentand/or afferent neural fibers) of the kidneys. Such incapacitation canbe long-term (e.g., permanent or for periods of months, years, ordecades) or short-term (e.g., for periods of minutes, hours, days, orweeks). Renal neuromodulation is expected to contribute to the systemicreduction of sympathetic tone or drive and/or to benefit at least somespecific organs and/or other bodily structures innervated by sympatheticnerves. Accordingly, renal neuromodulation is expected to be useful intreating clinical conditions associated with systemic sympatheticoveractivity or hyperactivity, particularly conditions associated withcentral sympathetic overstimulation. For example, renal neuromodulationis expected to efficaciously treat hypertension, heart failure, acutemyocardial infarction, metabolic syndrome, insulin resistance, diabetes,left ventricular hypertrophy, chronic and end stage renal disease,inappropriate fluid retention in heart failure, cardio-renal syndrome,polycystic kidney disease, polycystic ovary syndrome, osteoporosis,erectile dysfunction, and sudden death, among other conditions.

Renal neuromodulation can be electrically-induced, thermally-induced,chemically-induced, or induced in another suitable manner or combinationof manners at one or more suitable target sites during a treatmentprocedure. The target site can be within or otherwise proximate to arenal lumen (e.g., a renal artery, a ureter, a renal pelvis, a majorrenal calyx, a minor renal calyx, or another suitable structure), andthe treated tissue can include tissue at least proximate to a wall ofthe renal lumen. For example, with regard to a renal artery, a treatmentprocedure can include modulating nerves in the renal plexus, which layintimately within or adjacent to the adventitia of the renal artery.

Renal neuromodulation can include an electrode-based or transducer-basedtreatment modality alone or in combination with another treatmentmodality. As discussed herein, for example, electrode-based ortransducer-based treatment can include delivering electricity and/oranother form of energy to tissue at a treatment location to stimulateand/or heat the tissue in a manner that modulates neural function. Forexample, sufficiently stimulating and/or heating at least a portion of asympathetic renal nerve can slow or potentially block conduction ofneural signals to produce a prolonged or permanent reduction in renalsympathetic activity. A variety of suitable types of energy can be usedto stimulate and/or heat tissue at a treatment location. For example,neuromodulation in accordance with embodiments of the present technologycan include delivering RF energy, pulsed electrical energy, or anothersuitable type of energy in combination with the electrical energy. Anelectrode or transducer used to deliver this energy can be used alone orwith other electrodes or transducers in a multi-electrode ormulti-transducer array. Furthermore, the energy can be applied fromwithin the body (e.g., within the vasculature or other body lumens in acatheter-based approach) and/or from outside the body (e.g., via anapplicator positioned outside the body). Furthermore, energy can be usedto reduce damage to non-targeted tissue when targeted tissue adjacent tothe non-targeted tissue is subjected to neuromodulating cooling.

In certain embodiments, neuromodulation may utilize one or more devicesincluding, for example, catheter devices such as the Symplicity™catheter or Symplicity Spyral™ catheter mentioned previously (Medtronic,Inc.). Other suitable thermal devices are described in U.S. Pat. Nos.7,653,438, 8,347,891, and U.S. patent application Ser. No. 13/279,205,filed Oct. 21, 2011. Other suitable devices and technologies aredescribed in U.S. patent application Ser. No. 13/279,330, filed Oct. 23,2011, International Patent Application No. PCT/US2015/021835, filed Mar.20, 2015, and International Patent Application No. PCT/US2015/013029,filed Jan. 27, 2015. Further, electrodes (or other energy deliveryelements) can be used alone or with other electrodes in amulti-electrode array. Examples of suitable multi-electrode devices aredescribed in U.S. patent application Ser. No. 13/281,360, filed Oct. 25,2011, and U.S. Pat. No. 8,888,773. All of the foregoing patentreferences are incorporated herein by reference in their entireties.

Thermal effects can include both thermal ablation and/or non-ablativethermal alteration or damage (e.g., via sustained heating and/orresistive heating) to partially or completely disrupt the ability of anerve to transmit a signal. Such thermal effects can include the heatingeffects associated with electrode-based or transducer-based treatment.For example, a treatment procedure can include raising the temperatureof target neural fibers to a target temperature above a first thresholdto achieve non-ablative alteration, or above a second, higher thresholdto achieve ablation. The target temperature can be higher than aboutbody temperature (e.g., about 37° C.) but less than about 45° C. fornon-ablative alteration, and the target temperature can be higher thanabout 45° C. for ablation. Heating tissue to a temperature between aboutbody temperature and about 45° C. can induce non-ablative alteration,for example, via moderate heating of target neural fibers or of vascularor luminal structures that perfuse the target neural fibers. In caseswhere vascular structures are affected, the target neural fibers can bedenied perfusion resulting in necrosis of the neural tissue. Heatingtissue to a target temperature higher than about 45° C. (e.g., higherthan about 60° C.) can induce ablation, for example, via substantialheating of target neural fibers or of vascular or luminal structuresthat perfuse the target fibers. In some patients, it can be desirable toheat tissue to temperatures that are sufficient to ablate the targetneural fibers or the vascular or luminal structures, but less than about90° C. (e.g., less than about 85° C., less than about 80° C., or lessthan about 75° C.). Other embodiments can include heating tissue to avariety of other suitable temperatures.

IV. Related Anatomy and Physiology

As noted previously, the sympathetic nervous system (SNS) is a branch ofthe autonomic nervous system along with the enteric nervous system andparasympathetic nervous system. It is always active at a basal level(called sympathetic tone) and becomes more active during times ofstress. Like other parts of the nervous system, the sympathetic nervoussystem operates through a series of interconnected neurons. Sympatheticneurons are frequently considered part of the peripheral nervous system(PNS), although many lie within the central nervous system (CNS).Sympathetic neurons of the spinal cord (which is part of the CNS)communicate with peripheral sympathetic neurons via a series ofsympathetic ganglia. Within the ganglia, spinal cord sympathetic neuronsjoin peripheral sympathetic neurons through synapses. Spinal cordsympathetic neurons are therefore called presynaptic (or preganglionic)neurons, while peripheral sympathetic neurons are called postsynaptic(or postganglionic) neurons.

At synapses within the sympathetic ganglia, preganglionic sympatheticneurons release acetylcholine, a chemical messenger that binds andactivates nicotinic acetylcholine receptors on postganglionic neurons.In response to this stimulus, postganglionic neurons principally releasenoradrenaline (norepinephrine). Prolonged activation may elicit therelease of adrenaline from the adrenal medulla.

Once released, norepinephrine and epinephrine bind adrenergic receptorson peripheral tissues. Binding to adrenergic receptors causes a neuronaland hormonal response. The physiologic manifestations include pupildilation, increased heart rate, occasional vomiting, and increased bloodpressure. Increased sweating is also seen due to binding of cholinergicreceptors of the sweat glands.

The sympathetic nervous system is responsible for up- anddown-regulating many homeostatic mechanisms in living organisms. Fibersfrom the SNS innervate tissues in almost every organ system, providingat least some regulatory function to physiological features as diverseas pupil diameter, gut motility, and urinary output. This response isalso known as sympatho-adrenal response of the body, as thepreganglionic sympathetic fibers that end in the adrenal medulla (butalso all other sympathetic fibers) secrete acetylcholine, whichactivates the secretion of adrenaline (epinephrine) and to a lesserextent noradrenaline (norepinephrine). Therefore, this response thatacts primarily on the cardiovascular system is mediated directly viaimpulses transmitted through the sympathetic nervous system andindirectly via catecholamines secreted from the adrenal medulla.

Science typically looks at the SNS as an automatic regulation system,that is, one that operates without the intervention of consciousthought. Some evolutionary theorists suggest that the sympatheticnervous system operated in early organisms to maintain survival as thesympathetic nervous system is responsible for priming the body foraction. One example of this priming is in the moments before waking, inwhich sympathetic outflow spontaneously increases in preparation foraction.

A. The Sympathetic Chain

As shown in FIG. 9, the SNS provides a network of nerves that allows thebrain to communicate with the body. Sympathetic nerves originate insidethe vertebral column, toward the middle of the spinal cord in theintermediolateral cell column (or lateral horn), beginning at the firstthoracic segment of the spinal cord and are thought to extend to thesecond or third lumbar segments. Because its cells begin in the thoracicand lumbar regions of the spinal cord, the SNS is said to have athoracolumbar outflow. Axons of these nerves leave the spinal cordthrough the anterior rootlet/root. They pass near the spinal (sensingelement) ganglion, where they enter the anterior rami of the spinalnerves. However, unlike somatic innervation, they quickly separate outthrough white rami connectors which connect to either the paravertebral(which lie near the vertebral column) or prevertebral (which lie nearthe aortic bifurcation) ganglia extending alongside the spinal column.

In order to reach the target organs and glands, the axons should travellong distances in the body, and, to accomplish this, many axons relaytheir message to a second cell through synaptic transmission. The endsof the axons link across a space, the synapse, to the dendrites of thesecond cell. The first cell (the presynaptic cell) sends aneurotransmitter across the synaptic cleft where it activates the secondcell (the postsynaptic cell). The message is then carried to the finaldestination.

In the SNS and other components of the peripheral nervous system, thesesynapses are made at sites called ganglia, discussed above. The cellthat sends its fiber is called a preganglionic cell, while the cellwhose fiber leaves the ganglion is called a postganglionic cell. Asmentioned previously, the preganglionic cells of the SNS are locatedbetween the first thoracic (T1) segment and third lumbar (L3) segmentsof the spinal cord. Postganglionic cells have their cell bodies in theganglia and send their axons to target organs or glands.

The ganglia include not just the sympathetic trunks but also thecervical ganglia (superior, middle and inferior), which sendssympathetic nerve fibers to the head and thorax organs, and the celiacand mesenteric ganglia (which send sympathetic fibers to the gut).

1. Innervation of the Kidneys

As FIG. 10 shows, the kidney is innervated by the renal plexus (RP),which is intimately associated with the renal artery. The renal plexus(RP) is an autonomic plexus that surrounds the renal artery and isembedded within the adventitia of the renal artery. The renal plexus(RP) extends along the renal artery until it arrives at the substance ofthe kidney. Fibers contributing to the renal plexus (RP) arise from theceliac ganglion, the superior mesenteric ganglion, the aorticorenalganglion and the aortic plexus. The renal plexus (RP), also referred toas the renal nerve, is predominantly comprised of sympatheticcomponents. There is no (or at least very minimal) parasympatheticinnervation of the kidney.

Preganglionic neuronal cell bodies are located in the intermediolateralcell column of the spinal cord. Preganglionic axons pass through theparavertebral ganglia (they do not synapse) to become the lessersplanchnic nerve, the least splanchnic nerve, first lumbar splanchnicnerve, second lumbar splanchnic nerve, and travel to the celiacganglion, the superior mesenteric ganglion, and the aorticorenalganglion. Postganglionic neuronal cell bodies exit the celiac ganglion,the superior mesenteric ganglion, and the aorticorenal ganglion to therenal plexus (RP) and are distributed to the renal vasculature.

2. Renal Sympathetic Neural Activity

Messages travel through the SNS in a bidirectional flow. Efferentmessages may trigger changes in different parts of the bodysimultaneously. For example, the sympathetic nervous system mayaccelerate heart rate; widen bronchial passages; decrease motility(movement) of the large intestine; constrict blood vessels; increaseperistalsis in the esophagus; cause pupil dilation, piloerection (goosebumps) and perspiration (sweating); and raise blood pressure. Afferentmessages carry signals from various organs and sensing element receptorsin the body to other organs and, particularly, the brain.

Hypertension, heart failure and chronic kidney disease are a few of manydisease states that result from chronic activation of the SNS,especially the renal sympathetic nervous system. Chronic activation ofthe SNS is a maladaptive response that drives the progression of thesedisease states. Pharmaceutical management of therenin-angiotensin-aldosterone system (RAAS) has been a longstanding, butsomewhat ineffective, approach for reducing over-activity of the SNS.

As mentioned above, the renal sympathetic nervous system has beenidentified as a major contributor to the complex pathophysiology ofhypertension, states of volume overload (such as heart failure), andprogressive renal disease, both experimentally and in humans. Studiesemploying radiotracer dilution methodology to measure overflow ofnorepinephrine from the kidneys to plasma revealed increased renalnorepinephrine (NE) spillover rates in patients with essentialhypertension, particularly so in young hypertensive subjects, which inconcert with increased NE spillover from the heart, is consistent withthe hemodynamic profile typically seen in early hypertension andcharacterized by an increased heart rate, cardiac output, andrenovascular resistance. It is now known that essential hypertension iscommonly neurogenic, often accompanied by pronounced sympathetic nervoussystem overactivity.

Activation of cardiorenal sympathetic nerve activity is even morepronounced in heart failure, as demonstrated by an exaggerated increaseof NE overflow from the heart and the kidneys to plasma in this patientgroup. In line with this notion is the recent demonstration of a strongnegative predictive value of renal sympathetic activation on all-causemortality and heart transplantation in patients with congestive heartfailure, which is independent of overall sympathetic activity,glomerular filtration rate, and left ventricular ejection fraction.These findings support the notion that treatment regimens that aredesigned to reduce renal sympathetic stimulation have the potential toimprove survival in patients with heart failure.

Both chronic and end stage renal disease are characterized by heightenedsympathetic nervous activation. In patients with end stage renaldisease, plasma levels of norepinephrine above the median have beendemonstrated to be predictive for both all-cause death and death fromcardiovascular disease. This is also true for patients suffering fromdiabetic or contrast nephropathy. There is compelling evidencesuggesting that sensing element afferent signals originating from thediseased kidneys are major contributors to initiating and sustainingelevated central sympathetic outflow in this patient group; thisfacilitates the occurrence of the well-known adverse consequences ofchronic sympathetic over activity, such as hypertension, leftventricular hypertrophy, ventricular arrhythmias, sudden cardiac death,insulin resistance, diabetes, and metabolic syndrome.

(i) Renal Sympathetic Efferent Activity

Sympathetic nerves to the kidneys terminate in the blood vessels, thejuxtaglomerular apparatus and the renal tubules. Stimulation of therenal sympathetic nerves causes increased renin release, increasedsodium (Na⁺) reabsorption, and a reduction of renal blood flow. Thesecomponents of the neural regulation of renal function are considerablystimulated in disease states characterized by heightened sympathetictone and clearly contribute to the rise in blood pressure inhypertensive patients. The reduction of renal blood flow and glomerularfiltration rate as a result of renal sympathetic efferent stimulation islikely a cornerstone of the loss of renal function in cardio-renalsyndrome, which is renal dysfunction as a progressive complication ofchronic heart failure, with a clinical course that typically fluctuateswith the patient's clinical status and treatment. Pharmacologicstrategies to thwart the consequences of renal efferent sympatheticstimulation include centrally acting sympatholytic drugs, beta blockers(intended to reduce renin release), angiotensin converting enzymeinhibitors and receptor blockers (intended to block the action ofangiotensin II and aldosterone activation consequent to renin release)and diuretics (intended to counter the renal sympathetic mediated sodiumand water retention). However, the current pharmacologic strategies havesignificant limitations including limited efficacy, compliance issues,side effects and others.

(ii) Renal Sensory Afferent Nerve Activity

The kidneys communicate with integral structures in the central nervoussystem via renal sensory afferent nerves. Several forms of “renalinjury” may induce activation of sensory afferent signals. For example,renal ischemia, reduction in stroke volume or renal blood flow, or anabundance of adenosine enzyme may trigger activation of afferent neuralcommunication. As shown in FIGS. 11 and 12, this afferent communicationmight be from the kidney to the brain or might be from one kidney to theother kidney (via the central nervous system). These afferent signalsare centrally integrated and may result in increased sympatheticoutflow. This sympathetic drive is directed towards the kidneys, therebyactivating the RAAS and inducing increased renin secretion, sodiumretention, volume retention and vasoconstriction. Central sympatheticover activity also impacts other organs and bodily structures innervatedby sympathetic nerves such as the heart and the peripheral vasculature,resulting in the described adverse effects of sympathetic activation,several aspects of which also contribute to the rise in blood pressure.

The physiology therefore suggests that (i) modulation of tissue withefferent sympathetic nerves will reduce inappropriate renin release,salt retention, and reduction of renal blood flow, and that (ii)modulation of tissue with afferent sensory nerves will reduce thesystemic contribution to hypertension and other disease statesassociated with increased central sympathetic tone through its directeffect on the posterior hypothalamus as well as the contralateralkidney. In addition to the central hypotensive effects of afferent renaldenervation, a desirable reduction of central sympathetic outflow tovarious other sympathetically innervated organs such as the heart andthe vasculature is anticipated.

B. Additional Clinical Benefits of Renal Denervation

As provided above, renal denervation is likely to be valuable in thetreatment of several clinical conditions characterized by increasedoverall and particularly renal sympathetic activity such ashypertension, metabolic syndrome, insulin resistance, diabetes, leftventricular hypertrophy, chronic end stage renal disease, inappropriatefluid retention in heart failure, cardio-renal syndrome, and suddendeath. Since the reduction of afferent neural signals contributes to thesystemic reduction of sympathetic tone/drive, renal denervation mightalso be useful in treating other conditions associated with systemicsympathetic hyperactivity. Accordingly, renal denervation may alsobenefit other organs and bodily structures innervated by sympatheticnerves, including those identified in FIG. 9. For example, as previouslydiscussed, a reduction in central sympathetic drive may reduce theinsulin resistance that afflicts people with metabolic syndrome and TypeII diabetics. Additionally, patients with osteoporosis are alsosympathetically activated and might also benefit from the downregulation of sympathetic drive that accompanies renal denervation.

C. Achieving Intravascular Access to the Renal Artery

In accordance with the present technology, neuromodulation of a leftand/or right renal plexus (RP), which is intimately associated with aleft and/or right renal artery, may be achieved through intravascularaccess. As FIG. 13 shows, blood moved by contractions of the heart isconveyed from the left ventricle of the heart by the aorta. The aortadescends through the thorax and branches into the left and right renalarteries. Below the renal arteries, the aorta bifurcates at the left andright iliac arteries. The left and right iliac arteries descend,respectively, through the left and right legs and join the left andright femoral arteries.

As FIG. 14 shows, the blood collects in veins and returns to the heart,through the femoral veins into the iliac veins and into the inferiorvena cava. The inferior vena cava branches into the left and right renalveins. Above the renal veins, the inferior vena cava ascends to conveyblood into the right atrium of the heart. From the right atrium, theblood is pumped through the right ventricle into the lungs, where it isoxygenated. From the lungs, the oxygenated blood is conveyed into theleft atrium. From the left atrium, the oxygenated blood is conveyed bythe left ventricle back to the aorta.

As will be described in greater detail later, the femoral artery may beaccessed and cannulated at the base of the femoral triangle justinferior to the midpoint of the inguinal ligament. A catheter may beinserted percutaneously into the femoral artery through this accesssite, passed through the iliac artery and aorta, and placed into eitherthe left or right renal artery. This comprises an intravascular paththat offers minimally invasive access to a respective renal arteryand/or other renal blood vessels.

The wrist, upper arm, and shoulder region provide other locations forintroduction of catheters into the arterial system. For example,catheterization of either the radial, brachial, or axillary artery maybe utilized in select cases. Catheters introduced via these accesspoints may be passed through the subclavian artery on the left side (orvia the subclavian and brachiocephalic arteries on the right side),through the aortic arch, down the descending aorta and into the renalarteries using standard angiographic technique.

D. Properties and Characteristics of the Renal Vasculature

Since neuromodulation of a left and/or right renal plexus (RP) may beachieved in accordance with the present technology through intravascularaccess, properties and characteristics of the renal vasculature mayimpose constraints upon and/or inform the design of apparatus, systems,and methods for achieving such renal neuromodulation. Some of theseproperties and characteristics may vary across the patient populationand/or within a specific patient across time, as well as in response todisease states, such as hypertension, chronic kidney disease, vasculardisease, end-stage renal disease, insulin resistance, diabetes,metabolic syndrome, etc. These properties and characteristics, asexplained herein, may have bearing on the efficacy of the procedure andthe specific design of the intravascular device. Properties of interestmay include, for example, material/mechanical, spatial, fluiddynamic/hemodynamic and/or thermodynamic properties.

As discussed previously, a catheter may be advanced percutaneously intoeither the left or right renal artery via a minimally invasiveintravascular path. However, minimally invasive renal arterial accessmay be challenging, for example, because as compared to some otherarteries that are routinely accessed using catheters, the renal arteriesare often extremely tortuous, may be of relatively small diameter,and/or may be of relatively short length. Furthermore, renal arterialatherosclerosis is common in many patients, particularly those withcardiovascular disease. Renal arterial anatomy also may varysignificantly from patient to patient, which further complicatesminimally invasive access. Significant inter-patient variation may beseen, for example, in relative tortuosity, diameter, length, and/oratherosclerotic plaque burden, as well as in the take-off angle at whicha renal artery branches from the aorta. Apparatus, systems and methodsfor achieving renal neuromodulation via intravascular access shouldaccount for these and other aspects of renal arterial anatomy and itsvariation across the patient population when minimally invasivelyaccessing a renal artery.

In addition to complicating renal arterial access, specifics of therenal anatomy also complicate establishment of stable contact betweenneuromodulatory apparatus and a luminal surface or wall of a renalartery. For example, navigation can be impeded by the tight space withina renal artery, as well as tortuosity of the artery. Furthermore,establishing consistent contact is complicated by patient movement,respiration, and/or the cardiac cycle because these factors may causesignificant movement of the renal artery relative to the aorta, and thecardiac cycle may transiently distend the renal artery (i.e. cause thewall of the artery to pulse).

Even after accessing a renal artery and facilitating stable contactbetween neuromodulatory apparatus and a luminal surface of the artery,nerves in and around the adventia of the artery should be safelymodulated via the neuromodulatory apparatus. Effectively applyingthermal treatment from within a renal artery is non-trivial given thepotential clinical complications associated with such treatment. Forexample, the intima and media of the renal artery are highly vulnerableto thermal injury. As discussed in greater detail below, theintima-media thickness separating the vessel lumen from its adventitiameans that target renal nerves may be multiple millimeters distant fromthe luminal surface of the artery. Sufficient energy should be deliveredto or heat removed from the target renal nerves to modulate the targetrenal nerves without excessively cooling or heating the vessel wall tothe extent that the wall is frozen, desiccated, or otherwise potentiallyaffected to an undesirable extent. A potential clinical complicationassociated with excessive heating is thrombus formation from coagulatingblood flowing through the artery. Given that this thrombus may cause akidney infarct, thereby causing irreversible damage to the kidney,thermal treatment from within the renal artery should be appliedcarefully. Accordingly, the complex fluid mechanics and thermodynamicconditions present in the renal artery during treatment, particularlythose that may impact heat transfer dynamics at the treatment site, maybe important in applying energy (e.g., heating thermal energy) and/orremoving heat from the tissue (e.g., cooling thermal conditions) fromwithin the renal artery.

The neuromodulatory apparatus should also be configured to allow foradjustable positioning and repositioning of the energy delivery elementwithin the renal artery since location of treatment may also impactclinical efficacy. For example, it may be tempting to apply a fullcircumferential treatment from within the renal artery given that therenal nerves may be spaced circumferentially around a renal artery. Insome situations, a full-circle lesion likely resulting from a continuouscircumferential treatment may be potentially related to renal arterystenosis. Therefore, the formation of more complex lesions along alongitudinal dimension of the renal artery and/or repositioning of theneuromodulatory apparatus to multiple treatment locations may bedesirable. It should be noted, however, that a benefit of creating acircumferential ablation may outweigh the potential of renal arterystenosis or the risk may be mitigated with certain embodiments or incertain patients and creating a circumferential ablation could be agoal. Additionally, variable positioning and repositioning of theneuromodulatory apparatus may prove to be useful in circumstances wherethe renal artery is particularly tortuous or where there are proximalbranch vessels off the renal artery main vessel, making treatment incertain locations challenging. Manipulation of a device in a renalartery should also consider mechanical injury imposed by the device onthe renal artery. Motion of a device in an artery, for example byinserting, manipulating, negotiating bends and so forth, may contributeto dissection, perforation, denuding intima, or disrupting the interiorelastic lamina.

Blood flow through a renal artery may be temporarily occluded for ashort time with minimal or no complications. However, occlusion for asignificant amount of time should be avoided because to prevent injuryto the kidney such as ischemia. It could be beneficial to avoidocclusion all together or, if occlusion is beneficial to the embodiment,to limit the duration of occlusion, for example to 2-5 minutes.

Based on the above described challenges of (1) renal arteryintervention, (2) consistent and stable placement of the treatmentelement against the vessel wall, (3) effective application of treatmentacross the vessel wall, (4) positioning and potentially repositioningthe treatment apparatus to allow for multiple treatment locations, and(5) avoiding or limiting duration of blood flow occlusion, variousindependent and dependent properties of the renal vasculature that maybe of interest include, for example, (a) vessel diameter, vessel length,intima-media thickness, coefficient of friction, and tortuosity; (b)distensibility, stiffness and modulus of elasticity of the vessel wall;(c) peak systolic, end-diastolic blood flow velocity, as well as themean systolic-diastolic peak blood flow velocity, and mean/maxvolumetric blood flow rate; (d) specific heat capacity of blood and/orof the vessel wall, thermal conductivity of blood and/or of the vesselwall, and/or thermal convectivity of blood flow past a vessel walltreatment site and/or radiative heat transfer; (e) renal artery motionrelative to the aorta induced by respiration, patient movement, and/orblood flow pulsatility; and (f) the take-off angle of a renal arteryrelative to the aorta. These properties will be discussed in greaterdetail with respect to the renal arteries. However, dependent on theapparatus, systems and methods utilized to achieve renalneuromodulation, such properties of the renal arteries, also may guideand/or constrain design characteristics.

As noted above, an apparatus positioned within a renal artery shouldconform to the geometry of the artery. Renal artery vessel diameter,D_(RA), typically is in a range of about 2-10 mm, with most of thepatient population having a D_(RA) of about 4 mm to about 8 mm and anaverage of about 6 mm. Renal artery vessel length, L_(RA), between itsostium at the aorta/renal artery juncture and its distal branchings,generally is in a range of about 5-70 mm, and a significant portion ofthe patient population is in a range of about 20-50 mm. Since the targetrenal plexus is embedded within the adventitia of the renal artery, thecomposite Intima-Media Thickness, IMT, (i.e., the radial outwarddistance from the artery's luminal surface to the adventitia containingtarget neural structures) also is notable and generally is in a range ofabout 0.5-2.5 mm, with an average of about 1.5 mm. Although a certaindepth of treatment is important to reach the target neural fibers, thetreatment should not be too deep (e.g., >5 mm from inner wall of therenal artery) to avoid non-target tissue and anatomical structures suchas the renal vein.

An additional property of the renal artery that may be of interest isthe degree of renal motion relative to the aorta induced by respirationand/or blood flow pulsatility. A patient's kidney, which is located atthe distal end of the renal artery, may move as much as 4″ craniallywith respiratory excursion. This may impart significant motion to therenal artery connecting the aorta and the kidney, thereby requiring fromthe neuromodulatory apparatus a unique balance of stiffness andflexibility to maintain contact between the energy delivery element andthe vessel wall during cycles of respiration. Furthermore, the take-offangle between the renal artery and the aorta may vary significantlybetween patients, and also may vary dynamically within a patient, e.g.,due to kidney motion. The take-off angle generally may be in a range ofabout 30°-135°.

V. Conclusion

The above detailed descriptions of embodiments of the technology are notintended to be exhaustive or to limit the technology to the precise formdisclosed above. Although specific embodiments of, and examples for, thetechnology are described above for illustrative purposes, variousequivalent modifications are possible within the scope of thetechnology, as those skilled in the relevant art will recognize. Forexample, while steps are presented in a given order, alternativeembodiments may perform steps in a different order. The variousembodiments described herein may also be combined to provide furtherembodiments. All references cited herein are incorporated by referenceas if fully set forth herein.

From the foregoing, it will be appreciated that specific embodiments ofthe technology have been described herein for purposes of illustration,but well-known structures and functions have not been shown or describedin detail to avoid unnecessarily obscuring the description of theembodiments of the technology. Where the context permits, singular orplural terms may also include the plural or singular term, respectively.

Certain aspects of the present technology may take the form ofcomputer-executable instructions, including routines executed by acontroller or other data processor. In some embodiments, a controller orother data processor is specifically programmed, configured, and/orconstructed to perform one or more of these computer-executableinstructions. Furthermore, some aspects of the present technology maytake the form of data (e.g., non-transitory data) stored or distributedon computer-readable media, including magnetic or optically readableand/or removable computer discs as well as media distributedelectronically over networks. Accordingly, data structures andtransmissions of data particular to aspects of the present technologyare encompassed within the scope of the present technology. The presenttechnology also encompasses methods of both programmingcomputer-readable media to perform particular steps and executing thesteps.

Moreover, unless the word “or” is expressly limited to mean only asingle item exclusive from the other items in reference to a list of twoor more items, then the use of “or” in such a list is to be interpretedas including (a) any single item in the list, (b) all of the items inthe list, or (c) any combination of the items in the list. Additionally,the term “comprising” is used throughout to mean including at least therecited feature(s) such that any greater number of the same featureand/or additional types of other features are not precluded. Referenceherein to “one embodiment,” “an embodiment,” or similar formulationsmeans that a particular feature, structure, operation, or characteristicdescribed in connection with the embodiment can be included in at leastone embodiment of the present technology. Thus, the appearances of suchphrases or formulations herein are not necessarily all referring to thesame embodiment. Furthermore, various particular features, structures,operations, or characteristics may be combined in any suitable manner inone or more embodiments. It will also be appreciated that specificembodiments have been described herein for purposes of illustration, butthat various modifications may be made without deviating from thetechnology. Further, while advantages associated with certainembodiments of the technology have been described in the context ofthose embodiments, other embodiments may also exhibit such advantages,and not all embodiments need necessarily exhibit such advantages to fallwithin the scope of the technology. Accordingly, the disclosure andassociated technology can encompass other embodiments not expresslyshown or described herein.

I/We claim:
 1. A system, comprising: a neuromodulation catheterincluding— an elongated shaft having a distal portion configured to beintravascularly positioned at a target site within a blood vessel of ahuman patient, and a plurality of ablation electrodes spaced apart alongthe distal portion of the shaft, the plurality of ablation electrodesincluding a first ablation electrode and a second ablation electrode,wherein the ablation electrodes are configured to deliverneuromodulation energy to target nerves at or adjacent the target site;a plurality of reference electrodes configured to be positioned at thepatient's skin, the reference electrodes including a first referenceelectrode and a second reference electrode; a controller configured tobe communicatively coupled to the ablation electrodes and the referenceselectrodes, wherein the controller is further configured to— obtain afirst impedance measurement between the first ablation electrode and thefirst reference electrode, obtain a second impedance measurement betweenthe first ablation electrode and the second reference electrode, obtaina third impedance measurement between the second ablation electrode andthe first reference electrode, obtain a fourth impedance measurementbetween the second ablation electrode and the second referenceelectrode, and based on the first, second, third, and fourth impedancemeasurements: (a) identify a first electrode group consisting of thefirst ablation electrode and one of the first reference electrode andthe second reference electrode, and (b) identify a second electrodegroup consisting of the second ablation electrode and the other of thefirst reference electrode and the second reference electrode.
 2. Thesystem of claim 1 wherein the controller is configured to compare atleast one of the first, the second, the third, and the fourth impedancemeasurements to another of the first, the second, the third, and thefourth impedance measurements.
 3. The system of claim 2 wherein thecontroller is configured to identify the first electrode group and thesecond electrode group based on the comparison.
 4. The system of claim 1wherein the controller is configured to compare each of the first, thesecond, the third, and the fourth impedance measurements to each of theother first, second, third, and fourth impedance measurements.
 5. Thesystem of claim 4 wherein the controller is configured to identify thefirst electrode group and the second electrode group based on thecomparison.
 6. The system of claim 1 wherein the controller isconfigured to compare each of the first, the second, the third, and thefourth impedance measurements to one or more stored impedance values. 7.The system of claim 6 wherein the controller is configured to identifythe first electrode group and the second electrode group based on thecomparison.
 8. The system of claim 1 wherein the controller isconfigured to generate an impedance map of the blood vessel at thetarget site based on the first, the second, the third, and the fourthimpedance measurements.
 9. The system of claim 1, further comprising anenergy generator electrically coupled to the plurality of ablationelectrodes, the plurality of reference electrodes, and the controller,and wherein, in response to the identification of the first electrodegroup and the second electrode group, the controller is configured toautomatically cause the energy generator to: (a) deliver neuromodulationenergy via a first electrical current through the first electrode group,and (b) deliver neuromodulation energy via a second electrical currentthrough the second electrode group.
 10. The system of claim 9 whereinthe controller is an integral component of the energy generator and thecontroller and energy generator share a common housing.
 11. The systemof claim 1 wherein the controller is configured to indicate the firstelectrode group and the second electrode group to a user via a display.12. The system of claim 1 wherein: the controller is configured toobtain the first, the second, the third, and the fourth impedancemeasurements while the ablation electrodes are deliveringneuromodulation energy, and in response to the identification of thefirst electrode group and the second electrode group, the controller isconfigured to automatically cause the energy generator to— (a) stopdelivering neuromodulation energy via a first electrical current through(i) the first electrode and (ii) one of the plurality of referenceelectrodes that is not in the first electrode group, and (b) startdelivering neuromodulation energy via a second electrical currentthrough the first electrode group.
 13. The system of claim 1 wherein thedistal portion of the shaft is configured to be positioned in at leastone of a renal artery main vessel, a main bifurcation of the renalartery, and one or more renal branches distal of the main bifurcation ofthe renal artery.
 14. The system of claim 1 wherein the distal portionof the shaft is configured to transform into a spiral shape such that,when the distal portion is placed in the spiral shape while positionedwithin the blood vessel, at least one of the ablation electrodescontacts an inner surface of the blood vessel wall.
 15. The system ofclaim 1 wherein the number of reference electrodes is greater than thenumber of ablation electrodes.
 16. A method, comprising: positioning aplurality of reference electrodes at the skin of a human patient suchthat each of the reference electrodes is spaced apart from the otherreference electrodes, wherein the reference electrodes include a firstreference electrode and a second reference electrode; intravascularlypositioning a neuromodulation assembly within a blood vessel of thepatient at a treatment site, the neuromodulation assembly a firstablation electrode and a second ablation electrode spaced apart from thefirst ablation electrode; obtaining a first impedance measurementbetween the first ablation electrode and the first reference electrode;obtaining a second impedance measurement between the first ablationelectrode and the second reference electrode; obtaining a thirdimpedance measurement between the second ablation electrode and thefirst reference electrode; obtaining a fourth impedance measurementbetween the second ablation electrode and the second referenceelectrode; and based on the first, second, third, and fourth impedancemeasurements: (a) identifying a first electrode group consisting of thefirst ablation electrode and one of the first reference electrode andthe second reference electrode, and (b) identifying a second electrodegroup consisting of the second ablation electrode and the other of thefirst reference electrode and the second reference electrode.
 17. Themethod of claim 16, further comprising: in response to identifying thefirst electrode group and the second electrode group, automaticallydelivering neuromodulation energy to the treatment site by delivering afirst electrical current through the first electrode group anddelivering a second electrical current through the second electrodegroup.
 18. The method of claim 16 wherein positioning the plurality ofreference electrodes includes positioning at least one of the pluralityof reference electrodes at the patient's abdomen, at least one of theplurality of reference electrodes at the patient's torso, and at leastone of the plurality of reference electrodes at one or both of thepatient's legs.
 19. The method of claim 16, further comprising comparingat least one of the first, the second, the third, and the fourthimpedance measurements to another of the first, the second, the third,and the fourth impedance measurements.
 20. The method of claim 19wherein identifying the first electrode group and the second electrodegroup is based on the comparison.
 21. The method of claim 16, furthercomprising comparing each of the first, the second, the third, and thefourth impedance measurements to each of the other first, second, third,and fourth impedance measurements.
 22. The method of claim 21 whereinidentifying the first electrode group and the second electrode group isbased on the comparison.
 23. The method of claim 16, further comprisingcomparing each of the first, the second, the third, and the fourthimpedance measurements to one or more stored impedance values.
 24. Themethod of claim 23 wherein identifying the first electrode group and thesecond electrode group is based on the comparison.
 25. The method ofclaim 16, further comprising generating an impedance map of the bloodvessel at the target site based on the first, the second, the third, andthe fourth impedance measurements.
 26. The method of claim 16, furthercomprising indicating the first electrode group and the second electrodegroup to a user via a display.
 27. The method of claim 16 whereinobtaining the first, the second, the third, and the fourth impedancemeasurements occur while the ablation electrodes are deliveringneuromodulation energy.
 28. The method of claim 16, further comprising:in response to the identification of the first electrode group and thesecond electrode group, automatically causing the energy generator to:(a) stop delivering neuromodulation energy via a first electricalcurrent through (i) the first electrode and (ii) one of the plurality ofreference electrodes that is not in the first electrode group, and (b)start delivering neuromodulation energy via a second electrical currentthrough the first electrode group.
 29. The method of claim 16 whereinintravascularly positioning the neuromodulation assembly includespositioning the neuromodulation assembly in at least one of a renalartery main vessel, a main bifurcation of the renal artery, and one ormore renal branches distal of the main bifurcation of the renal artery.